Iodine-125 interstitial brachytherapy after tumor excision: an alternative eye-sparing surgery for lacrimal gland carcinoma

Background: To describe the preliminary suppressive effects of iodine-125 brachytherapy for malignant lacrimal gland tumors after excision. Methods: The study recruit 9 patients with lacrimal gland carcinoma from May 2017 to December 2020. All patients underwent eye-sparing surgical tumor resection first and then received iodine-125 interstitial brachytherapy to prevent tumor recurrence. We look over whether tumor recurred or metastasized by detecting the visual function and CT/MRI/PET-MRI of every patient. Results ： 1 patient was lost visit. The median follow-up period was 29 months of other 8 patients (range, 7-43 months). One patient experienced recurrence two years later but was free from local disease after iodine-125 seeds were implanted one more time. The vision of one female patient was lost due to the seeds moving to the optic nerve. In the remaining 6 patients, the vision was no changed, and CT/MRI showed no tumor was recurrenced. Conclusions: Permanent iodine-125 strip implantation in the orbit can be used as an alternative eye-sparing surgery for malignant lacrimal gland tumors after tumor excision. It can control tumor recurrence and maintenance of vision and good cosmesis.


Background
Primary lacrimal gland carcinoma are rare, including adenoid cystic carcinoma (ACC), pleomorphic adenocarcinoma, and denovo adenocarcinoma (ACA), ACC accounts for 60% of lacrimal gland malignant tumors. Its malignant degree is high, and it is easy to relapse, bony invasion, late metastasis and even death after operation [1][2][3]. Regardless of the any topical treatment, the estimated 5-year mortality rate is 50% [2,4].
About 80% of the patients have varying degrees of bone invasion [5], Orbital exenteration is the traditional surgical treatment, sometimes with removal of the involved bony walls if necessary [6], and followed by radiotherapy after operation.
More recently, the application of various new techniques have changed the mode of diagnosis and treatment of adenoid cystic carcinoma of the lacrimal gland.
Eye-sparing surgery combined with adjuvant radiation therapy or chemotherapy have been more and more popular in treatment of malignant lacrimal gland tumors.
Various types of radiation therapy are recommended, including external-beam radiation therapy, brachytherapy and proton therapy [6,8]. Interstitial brachytherapy is widely used in prostate cancer, meningioma, pancreas and some orbital tumors [8][9][10][11]. Include ciliochoroidal melanoma, retinoblastoma, malignant lacrimal sac tumours and so on [12,13]. But only one article has reported the effects of iodine-125 (I-125) plaque brachytherapy in the treatment of ACC [14]. In this study, 9 patients underwent tumor excision, and all were treated with radioactive I-125 seed implantation 1 month later. Visual function (eg. fundus photography, fluorescein angiography, optical coherence tomography), local recurrence, distant metastases, and survival were assessed to evaluate the effects of I-125 seed treatment of lacrimal gland carcinoma. Informed consents and photographs in verbal form was obtained from all patients at the follow-up visit.

Materials
The I-125 radioactive particles were obtained from Tianjin Saide Medicine Co.

Surgical treatments
Hematologic examination was underwent for all patients, orbital computed tomography (CT) and magnetic resonance imaging (MRI) were performed before the first operation. Ultrasonography of abdominal and neck lymph nodes ruled out multiple organ involvement (kidneys, pancreas, retroperitoneum). Eye-sparing surgery was performed with standard general anesthesia. The tumor and invaded bone were resected carefully and completely during the operation.
After the pathology was confirmed, the 4 earliest patients were assessed, and the seeds were inserted into the orbital tissue directly. In the other patients, the I-125 strips were implanted in the subperiosteum near the tumor. I-125 seeds were loaded in PICC tubes (PICC: peripherally inserted central catheter) as radioactive treatment strip. I-125 strips need processing to prevent particles from falling out.
That makes easier to remove the implant in the future, if necessary.
The activity and numbers of the I-125 particles intended to be implanted depend on tumor size. It was calculated using the following formula in our early article [9]: seed number = (tumor length + width + height)/3×5/ a mCi (a=0.6~0.8). All patients in this study didn't received any other treatment after the operation.

Patient characteristics
The histologic subtypes of tumors in all patients was assessed. The histologic diagnoses were as follows: 5 patients had ACC, and 4 patients had de novo ACA. The clinical information of patients is summarized in Table 1.

Visual function
Except for the earliest patient, one patient was lost to follow-up. All other patients were followed for 29 months medially. The vision of the fourth patient was lost intermittently 1 year later and finally lost. The vision, FFA, OCT and fundus photography results of all other patients did not change (Fig. 1). No radiation cataracts, glaucoma or diplopia occurred. All patients had slight xerophthalmia and recovered with artificial tears. They all had good cosmesis.

Tumor
At 1, 3, 6, and 12 months after the operation, CT/MRI/PET-MRI of the operated orbit was performed and then every 6 months thereafter. The tumor of the second patient recurred in the subcutaneous tissue of the orbit 2 years later, but without distant metastases. Then, surgery and I-125 seeds implantation were performed in the orbit once more. External radiotherapy (ER) for the subcutaneous tumor lasted 20 days, and the target dose was 30 Gy. MRI showed no recurrence sign until now, and vision was still 60/100 (Fig. 2). All CT/MRI scans of the other 6 patients did not show local tumor recurrence. The lymph nodes in the neck did not show swelling on ultrasonography.

Discussion
Despite active local treatment, ACC is invasive and the prognosis is poor, partly due to early perineural spread (approximately 75% of cases) and bony involvement. [14,15]. The rates of local and regional recurrences and late distant metastases in patients with ACC are high, and 50% of patients die of the disease even with modern treatments [16,17]. For lacrimal gland carcinoma, the expectation of treatment is to locally control regeneration and prevent distant metastasis. Tumor tissue can often infiltrate the orbital soft tissue because the tumor lacks a true capsule [14]. Orbital exenteration has been the most common method for the treatment of lacrimal gland malignant tumors. If bone is involved, it should be removed at the same time.
However, Woo KI et al. showed that extensive surgery does not decrease the risk of distant metastasis and does not seem to improve survival [4]. Many patients are young and have good vision in the ipsilateral eye. Therefore, eye-sparing surgery for lacrimal gland malignant tumors has been advocated. Radiation therapy after surgery may be a reasonable option.
Radiation therapy includes external-beam radiation therapy, proton therapy, and brachytherapy. ER may produce several side-effects on ocular and periocular structures, like substantial visual loss, including glaucoma, dry eyes, cataracts, radiation retinopathy, and so on [18,19,20]. Proton therapy is too expensive for patients in developing countries. Therefore, brachytherapy is a better option and was chosen in our treatment.
I-125 is a common radioactive therapy used in some kinds of unresectable solid tumors. At the same time, I-125 plaques was also used in some ocular tumors and orbital rhabdomyosarcoma. We also reported articles for the treatment of lacrimal sac malignant tumors [9]. patients, while one patient needs further surgery to remove recurring tissue [14]. In contrast to impermanent I-125 plaque radiotherapy, we put the I-125 seeds into the PICC tubes as radioactive treatment strip and implanted them under the orbital periosteum permanently. On the one hand, it ensured that all residual tumor cells were treated. On the other hand, the seeds were away from the eyeball and ensured that vision was stable.
In the process of exploring the method of seed implantation, the seeds were implanted into the orbital tissue directly in the 4 earliest patients. The fourth patient's vision was lost intermittently because the seeds moved to the optic nerve and thus caused vision loss 1 year later. Therefore, I-125 seed strips under the periosteum were used in the subsequent 5 patients, and vision was stable in these patients (Fig. 3). After 6 months, the seed strips could be whether took out or implanted again according the patient's condition.
The ACC tumor of the second patient recurred in and out of the orbit 2 years later, which was related to the smaller seed number and activity in the first operation.
The patient received tumor excision and I-125 seed implantation once more. The out of orbit tumor was treated with ER. The vision was kept at 60/100, and the tumor had no recurrence during the follow-up time.
Pain is often suggestive of malignant lacrimal gland lesions, including ACC and ACA, and may be secondary to bone or orbital nerve involvement [21]. All patients had no pain after the operation, which may be related to subperiosteal implantation of the I-125 seeds. In this study, 6 (65%) patients had xerophthalmia in the ipsilateral eye. It is possible that radiotherapy have some effects on the eyes. All of them recovered with artificial tears.
In recruited patients with lacrimal gland carcinoma, the use of I-125 seeds radiotherapy combined with eye-sparing surgery has a good control of the tumor, while maintaining visual function, and the radiation-induced ocular toxicity is minimal. Early diagnosis and safer and more effective treatment have greatly improved the prognosis, but long-term follow-up is especially necessary for patients with lacrimal gland carcinoma. Therefore, although this new radiotherapy for lacrimal gland carcinoma (such as adjuvant or primary therapy) have many advantages, long-term follow-up is still required to determine late recurrence, distant metastasis and survival rates.

Consent for publication
Written informed consent was obtained from all patients for publication of this artical and any accompanying images. A copy of the written consent form is available for review from the Editor of this journal.

Availability of data and materials
The data of this study can be obtained from the corresponding author upon reasonable request.   Two methods of I-125 seed implantation. The seeds were implanted into the orbital tissue directly, but the seeds moved to the optic nerve and thus caused vision loss 1

Figure Legends
year later (a, b: arrow: the I-125 seeds). I-125 seed strips were stable under the periosteum of the orbit, and vision was not changed (c, d: arrow: the I-125 seed strips).